Ionising radiation is widely used to treat neoplastic disease, but its effectiveness appears often to be limited by the presence of radioresistant hypoxic cells in tumours. At present there is no generally-useful method for eliminating these hypoxic tumour cells. One approach, being evaluated clinically at present, is the use of compounds which are selectively toxic to cells under hypoxic conditions. The most important compounds of this type are known as bioreductive drugs (BD) because they are activated metabolically by enzymatic reduction to form cytotoxic products under hypoxic conditions. In general, the selectivity of these compound, to hypoxic cells is a consequence of reoxidation of the initial one-electron reduction product by dioxygen, resulting in futile redox cycling and suppression of net reduction in oxygenated tissue.
The mechanism of activation of most BD is as follows: ##STR1##
BD are however likely to have two main limitations in clinical use.
The first of these is that enzymatic activation of BD is not restricted exclusively to hypoxic environments in tumours, and these drugs will therefore have some toxic effect against normal, well-oxygenated tissues. In particular, reductive activation by oxygen-insensitive pathways (obligate 2-electron reduction, which bypasses the O.sub.2 -sensitive intermediate) may sometimes be a limitation.
A second limitation of BD is that, to be effective, enzymes capable of activating the bioreductive drug must be expressed at a high level in the tumour. This is not a condition which will be met by all tumours.
An alternative approach involving activation of a prodrug was reported by Nishimoto et al in J. Med. Chem 35:2712-2715 (1992). In this approach, radiolytic activation of a 5-fluorouracil (5-FU) dimer was suggested as a radiosensitisation strategy in mice. However, it is apparent that radiolytic activation of the reported 5-FU dimer would not be clinically effective as the yield of cytotoxin was too low (a theoretical maximum yield in the order of 2 .mu.mol/kg at the radiation dose used (20Gy)).